Unit dosage of apadenoson

ABSTRACT

The present invention provides a unit dosage of Apadenoson, a pharmacological stress agent, and use of the same as a pharmacologic agent for myocardial perfusion imaging.

CROSS-REFERENCE TO RELATED APPLICATIONS

The present application is a continuation of U.S. patent applicationSer. No. 15/181,235, filed on Jun. 13, 2016, which is a continuation ofU.S. patent application Ser. No. 14/103,130, filed on Dec. 11, 2013 (nowU.S. Pat. No. 9,415,058), which is a divisional of U.S. patentapplication Ser. No. 13/544,364, filed on Jul. 9, 2012, which is acontinuation of U.S. patent application Ser. No. 12/496,949, filed onJul. 2, 2009, now abandoned, which claims the priority benefits of U.S.Provisional Applications No. 61/078,169, filed Jul. 3, 2008 and No.61/155,937, filed Feb. 27, 2009, which are expressly incorporated fullyherein by reference.

FIELD OF THE INVENTION

The present invention relates to a unit dosage of Apadenoson, apharmacological stress agent, and use of the same as a pharmacologicagent for myocardial perfusion imaging.

BACKGROUND OF THE INVENTION

Apadenoson, shown below, was first described as a pharmacologic stressagent

that can be used in clinical perfusion imaging techniques (e.g., fordiagnosing and assessing the extent of coronary artery disease) in U.S.Pat. No. 6,322,771. This agent has since been taken into Phase I and IIclinical trials. In 2005, Dr. Hendel et al reported to the AmericanHeart Association on the preliminary results of 127 patient SPECTTc^(99m) sestamibi imaging studying comparing adenosine with Apadenosonusing either 1 μg/kg or 2 μg/kg intravenous boluses of Apadenoson. Thereport concluded that Apadenoson was safe and well-tolerated and worthyof Phase III evaluation. In 2006, Dr. Kern et al reported to theAmerican Heart Association the results of a Phase II study ofApadenoson, one goal of which was to determine an appropriate dose forPhase III clinical trials. Intravenous bolus dosages of 0.5, 1.0, 2.0,and 2.5 μg/kg were studied. For a patients, the average peak velocityfor coronary blood flow was shown to increase with a correspondingincrease in dosage from 0.5 to 2 μg/kg (see FIG. 1). In light of thisdata, it was believed that Apadenoson would need to be administered on aweight basis, not a unit dose basis.

There are inherent limitations and opportunities for operator error whenparenterally administering a pharmaceutical agent on a weight basis.This type of dosing requires calculating the amount of agent toadminister based on a patient's weight, administering the calculatedamount from a larger dose, and disposing of any left over agent. Thus,it is desirable and beneficial for a pharmaceutical agent to be providedin a unit dose.

SUMMARY OF THE INVENTION

The present invention provides a novel unit dose of Apadenoson suitablefor parenteral administration.

The present invention also provides a novel method of diagnosingmyocardial dysfunction using a unit dose of Apadenoson as apharmacologic stress agent.

These and other aspects of the present invention have been accomplishedin view of the discovery that no dose response curve is seen when 1μg/kg or 2 μg/kg of Apadenoson is administered.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows the average peak flow wire velocity of one patient from aPhase II clinical trial study. In this Phase II study in 100 patients,conducted by Dr. Morton Kern, an independent investigator at UC Irvine,adenosine was administered by intracoronary injection, and coronaryblood flow velocity was monitored with a flow wire. On the left, thethree injections of adenosine increased blood flow velocity consistentwith the well characterized pharmacology of adenosine. On the right,increasing bolus doses of Apadenoson, at doses shown to be safe,achieved peak flow equivalent to adenosine.

FIG. 2 shows the average peak flow wire velocity of 33 patients from thestudy described in FIG. 1.

DETAILED DESCRIPTION OF THE INVENTION

The previously reported increase in coronary blood flow velocity (CBFV)corresponding to an increase in dose of Apadenoson from 0.5 to 2 μg/kgwas based on the increase in CBFV in a limited number of patients (seeFIG. 1). However, it has now been found that if one considers the entiresample of patients, as shown in FIG. 2, then at dose ≧1 μg/kg and inparticular between 1 and 2.5 μg/kg no dose response is seen. In light ofthis, Applicant has surprisingly discovered that instead of theweight-based dosing predicted by the results reported in FIG. 1,Apadenson can actually be administered via a unit dose.

Thus, in an embodiment, the present invention provides a novel unit doseof Apadenoson, comprising: (a) Apadenoson and (b) a pharmaceuticallyacceptable carrier, wherein the unit dose is suitable for parenteraladministration.

In another embodiment, the unit dose is suitable for intravenousadministration.

In another embodiment, the amount of Apadenoson present in the unit doseis selected from 76, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, 87, 88, 89,90, 91, 92, 93, 94, 95, 96, 97, 98, 99, 100, 101, 102, 103, 104, 105,106, 107, 108, 109, 110, 111, 112, 113, 114, 115, 116, 117, 118, 119,120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133,134, 135, 136, 137, 138, 139, 140, 141, 142, 143, 144, 145, 146, 147,148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161,162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173, 174, and 175μg. Additional examples of the weight of Apadenoson present include (a)100, 110, 120, 130, 140, and 150 μg; (b) 100 μg; and (c) 150 μg.

In another embodiment, the amount of Apadenoson present in the unit doseis in the range selected from 115, 116, 117, 118, 119, 120, 121, 122,123, 124, to 125 μg. Additional examples of the weight of Apadenosonpresent include (a) 115, 120, and 125 μg and (b) 120 μg.

In another embodiment, the pharmaceutical carrier, comprises: acyclodextrin. Examples of cyclodextrins include α-CD or derivativesthereof (e.g., α-hydroxypropyl-CD (HP-α-CD)), β-CD or derivativesthereof (e.g., β-hydroxypropyl-CD (HP-β-CD), methylated β-cyclodextrin,hydroxyethyl-β-cyclodextrin, and sulfobutylether β-CD), and γ-CD orderivatives thereof (e.g., γ-hydroxypropyl-CD (HP-γ-CD)).

Examples of the concentration of CD (e.g., hydroxypropyl-β-cyclodextrin)include being within the range selected from (a) about 0.1, 0.2, 0.3,0.4, 0.5, 0.6, 0.7, 0.8, 0.9, 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10% w/v;(b) about 0.5, 0.6., 0.7, 0.8, 0.9, 1, 2, 3, to 4% w/v; (c) about 1%w/v; and, (d) about 2% w/v of the final formulation.

In another embodiment, the pharmaceutical carrier, comprises: bufferedsaline. A useful buffer is a citrate buffer (e.g., sodium citrate).Citric acid can be useful to adjust the pH of the unit dose. As anexample, the pharmaceutical carrier, comprises: buffered saline,comprising: saline, sodium citrate, and citric acid. One would recognizethat citric acid may not be present in the final unit dose due toionization.

In another embodiment, the pH of the unit dose is selected from 4.6,4.7, 4.8, 4.9, to 5.0. Another example of the pH of the unit does is4.8.

In another embodiment, the volume of the unit dose is selected from 1,1.5, 2, 2.5, 3, 3.5, 4, 4.5, and 5 mL. Another example of the volume isfrom 2, 3, 4, to 5 mL.

In another embodiment, the unit dose, comprises:

-   -   (a) 100 μg Apadenoson;    -   (b) a pharmaceutically acceptable carrier, comprising:        -   (b_(i)) 2% w/v HP-β-CD;        -   (b_(ii)) sodium citrate buffer in an amount to buffer the            unit dose to pH 4.8; and,        -   (b_(iii)) saline in an amount to form a 1-5 mL unit dose.

In another embodiment, the unit dose, comprises:

-   -   (a) 100 μg Apadenoson;    -   (b) a pharmaceutically acceptable carrier, comprising:        -   (b_(i)) 1% w/v HP-β-CD;        -   (b_(ii)) sodium citrate buffer in an amount to buffer the            unit dose to pH 4.8; and,        -   (b_(iii)) saline in an amount to form a 1-5 mL unit dose.

In another embodiment, the unit dose, comprises:

-   -   (a) 150 μg Apadenoson;    -   (b) a pharmaceutically acceptable carrier, comprising:        -   (b_(i)) 2% w/v HP-β-CD;        -   (b_(ii)) sodium citrate buffer in an amount to buffer the            unit dose to pH 4.8; and,        -   (b_(iii)) saline in an amount to form a 1-5 mL unit dose.

In another embodiment, the unit dose, comprises:

-   -   (a) 150 μg Apadenoson;    -   (b) a pharmaceutically acceptable carrier, comprising:        -   (b_(i)) 2% w/v HP-β-CD;        -   (b_(ii)) sodium citrate buffer in an amount to buffer the            unit dose to pH 4.8; and,        -   (b_(iii)) saline in an amount to form a 1-5 mL unit dose.

The unit dose of the present invention can be filled into any usefulcontainer for storage, transportation, and usage. An example of a usefulcontainer is a syringe body.

In another embodiment, the present invention provides a novel method ofdiagnosing myocardial perfusion abnormalities in a mammal, comprising:

-   -   (a) parenterally administering to the mammal a unit dose of        Apadenoson; and    -   (b) performing a technique on the mammal to detect the presence        of coronary artery stenoses, assess the severity of coronary        artery stenoses, or a combination thereof.

In another embodiment, the patient weighs at least 40 kg.

In another embodiment, the administration is intravenous administration.

In another embodiment, the technique is an imaging technique selectedfrom: planar or single photon emission computed tomography (SPECT),gamma camera scintigraphy, positron emission tomography (PET), nuclearmagnetic resonance (NMR) imaging, magnetic resonance imaging (MRI)imaging, perfusion contrast echocardiography, digital subtractionangiography (DSA), and ultrafast X-ray computed tomography (CINE CT).

In another embodiment, the present invention provides a prefilledsyringe, comprising: a syringe and a unit dose of Apadenoson,comprising: (a) Apadenoson and (b) a pharmaceutically acceptablecarrier, wherein the unit dose is suitable for parenteraladministration. The syringe can be any known syringe useful forparenteral administration. For example, the syringe can comprise: a bodyand a plunger movably disposed within the body. The body can becylindrical with a first open end to receive the plunger and a secondend opposite the first, with the second end modified with an openingsufficient for the unit dose to pass through. The syringe can furthercomprise: a needle (e.g., an injection needle). The needle can bedetachably connected to or permanently fixed to the body. A needle guardcan also be present

In another embodiment, the present invention provides a novel unit doseof Apadenoson for use in medical therapy.

In another embodiment, the present invention provides a novel use of aunit dose of Apadenoson for the manufacture of a medicament for use indiagnosing myocardial perfusion abnormalities in a mammal.

The Apadenoson unit dose of the present invention can be administered asa pharmacological stress agent and used in conjunction with any one ofseveral noninvasive diagnostic procedures to measure aspects ofmyocardial, coronary, and/or ventricular perfusion. Aspects that can bemeasured include coronary artery stenoses, myocardial dysfunction (e.g.,myocardial ischemia, coronary artery disease, ventricular dysfunction,and differences in blood flow through disease-free coronary vesselsand/or stenotic coronary vessels), myocardial contractile dysfunction,the presence of regional wall motion abnormalities, the functionalsignificance of stenotic coronary vessels, coronary artery disease,ischemic ventricular dysfunction, and vasodilatory capacity (reservecapacity) of coronary arteries in humans. Radiopharmaceuticals aretypically used in diagnostic method methods. The radiopharmaceuticalagent may comprise, for example, a radionuclide selected from the groupconsisting of thallium-201, technetium-99m, nitrogen-13, rubidium-82,iodine-123 and oxygen-15.

Any embodiment or feature of the present invention whether characterizedas preferred or not characterized as preferred may be combined with anyother aspect or feature of the invention, whether such other feature ischaracterized as preferred or not characterized as preferred.

Definitions

The examples provided in this application are non-inclusive unlessotherwise stated. They include but are not limited to the recitedgroups.

Unit dose means the amount of a medication administered to a patient ina single dose. A unit dose is typically independent of the weight of thepatient or may be associated with a specified weight range (e.g., ≧40kg).

The indefinite articles “a” and “an” mean “at least one” or “one ormore” when used in this application, including the claims, unlessspecifically indicated otherwise.

Mammal and patient covers warm blooded mammals that are typically undermedical care (e.g., humans and domesticated animals). Examples ofmammals include (a) feline, canine, equine, and bovine and (b) human.

Parenteral includes intravenous, intramuscular, and subcutaneous routes.

Dosage and Formulation

Sterile injectable solutions are typically prepared by incorporating theactive compound in the required amount in the appropriate solvent withvarious of the other ingredients enumerated above, as required, followedby filter sterilization (or some other form of sterilization). In thecase of sterile powders for the preparation of sterile injectablesolutions, the methods of preparation include vacuum drying and thefreeze drying techniques, which yield a powder of the active ingredientplus any additional desired ingredient present in the previouslysterile-filtered solutions.

All patents, patent applications, books and literature cited in thespecification are hereby incorporated by reference in their entirety. Inthe case of any inconsistencies, the present disclosure, including anydefinitions therein will prevail.

Numerous modifications and variations of the present invention arepossible in light of the above teachings. It is therefore to beunderstood that within the scope of the appended claims, the inventionmay be practiced otherwise that as specifically described herein.

1. (canceled)
 2. A method of chemically inducing stress and diagnosingmyocardial perfusion abnormalities in a mammal, comprising: (a)selecting a unit dose of Apadenoson between about 76-175 ug for themammal wherein the mammal's weight falls within a specified weight rangeand the unit dose comprises: Apadenoson and a pharmaceuticallyacceptable carrier; (b) administering the unit dose to the mammal; and(c) performing a technique to detect the presence of coronary arterystenoses in the mammal, to assess the severity of coronary arterystenoses in the mammal, or a combination thereof, so as to diagnosemyocardial perfusion abnormalities in the mammal.
 3. The method of claim2, wherein the unit dose further contains an effective amount ofβ-hydroxypropyl-cyclodextrin (HP-β-CD).
 4. The method of claim 3,wherein the amount of HP-β-CD is about 0.1-10% w/v of the finalformulation.
 5. The method of claim 4, wherein the amount of HP-β-CD is1% w/v.
 6. The method of claim 2, wherein the dose of Apadenoson is 76μg.
 7. The method of claim 2, wherein the dose of Apadenoson is 110 μg.8. The method of claim 2, wherein the dose of Apadenoson is 115 μg. 9.The method of claim 2, wherein the dose of Apadenoson is 120 μg.
 10. Themethod of claim 2, wherein the dose of Apadenoson is 125 μg.
 11. Themethod of claim 2, wherein the dose of Apadenoson is 130 μg.
 12. Themethod of claim 2, wherein the dose of Apadenoson is 140 μg.
 13. Themethod of claim 2, wherein the unit dose is 1 mL in volume.
 14. Themethod of claim 2, wherein the unit dose is 2 mL in volume.
 15. Themethod of claim 2, wherein the unit dose is 3 mL in volume.
 16. Themethod of claim 2, wherein the unit dose is 4 mL in volume.
 17. Themethod of claim 2, wherein the unit dose is 5 mL in volume.
 18. Themethod of claim 2, wherein the dose of Apadenoson is selected on thebasis of a single weight of Apadenoson being effective in previouslytested mammals having a range of different weights.
 19. The method ofclaim 2, wherein the unit dose further contains sodium citrate buffer.20. The method of claim 19, wherein sodium citrate buffer is present inan amount to buffer the unit dose to pH selected from 4.6-5.0.
 21. Themethod of claim 19, wherein sodium citrate buffer is present in anamount to buffer the unit dose to pH 4.8.